Morphine is currently the most commonly used analgesic in the treatment of medium and high-intensity pain. At the level of the central nervous system three main classes of opioid receptors are distinguished: μ (mu), κ (kappa) and δ (delta). Morphine, like other opioids, mainly has an effect on the central nervous system and the digestive system via μ-opioid receptors. Two sub-types of μ receptors exist: type μ1 with very high affinity and low capacity, and type μ2 with low affinity and high capacity (Pasternak & Wood, 1986. Life Sci 38: 1889-1898). The bond with the μ1 receptors causes an analgesic reaction of the supraspinal type and reduction of the turnover of acetylcholine, while the bond with the μ2 receptors leads to an analgesic reaction of the spinal type and is responsible for respiratory depression and the inhibition of intestinal transit.
The mechanisms by which morphine exerts its analgesic action are still not completely clear. It is known that it undergoes a significant metabolism which leads to metabolites, some of which contribute to its analgesic action. The liver appears to be the main site of its biotransformation. Morphine principally undergoes an enantioselective glucuronidation catalyzed by UDP-glucuronyltransferase (UGT) which leads to the formation of two metabolites: morphine-3-glucuronide (hereafter also called “M3G”) and morphine-6-glucuronide (hereafter also called “M6G”).
It has been demonstrated that the modification of the 3-hydroxy position of morphine reduces analgesic activity, while modification of the 6-hydroxy position can, by contrast, increase analgesic activity (Aderjan & Skopp, 1998, Therapeutic Drug Monitoring 20: 561-569).
Thus, M3G has no affinity for the opioid receptors and does not participate in the analgesic activity of morphine.
On the other hand, morphine-6-glucuronide has a high affinity for the opioid receptors and it has been demonstrated that it has an analgesic effect both in rodents and in humans.
M6G has been described as an analgesic which is more powerful than morphine itself after a central administration (Paul et al., 1989. J Pharmacol. Exp. Ther. 49; 6280-6284; Frances et al., 1992. J Pharmacol. Exp. Ther. 262; 25-31) and has the same activity by systemic route. Studies of the ligand-opiate receptor bond carried out in vitro have shown that M6G bonded with the opioid receptors and that it had 1 to 5 times less affinity for μ receptors than morphine (Christensen & Jorgensen 1987. Pharmacol Toxicol. 60: 75-76; Frances et al., 1992 J Pharmacol. Exp. Ther. 262; 25-31).
Other morphine metabolites, in particular normorphine, have shown some analgesic activity. However, these other metabolites are present in low concentrations and are not capable of contributing in a significant fashion to the overall effect of morphine.
However, although it is very effective, the treatment of pain with morphine has undesirable side effects such as: respiratory depression, inhibition of intestinal transit, nausea, vomiting, and especially dependence syndrome and induction of tolerance.
Therefore it was sought to develop other active substances, presenting an analgesic effectiveness comparable to morphine, but not having all or some of its undesirable side effects.
Of course, due to its analgesic activity described above, it has been proposed to use M6G as a substitute for morphine.
In this regard, reference can be made to International Application WO 95/05831 relating to the use of a pharmaceutical composition for oral administration, containing M6G, for the treatment of pain.
International Application WO 99/64430 describes a method for the synthesis of M6G and its intermediates. U.S. Pat. No. 5,621,087 describes a novel method for the preparation of M6G or some of its derivatives.
M6G, which, as has been seen, has analgesic properties comparable to morphine, has the advantage of reducing nausea and vomiting. However, M6G does not contribute to the prevention of other undesirable effects of morphine, namely respiratory depression and dependence syndrome (Osborne et al., 1992. Br. J. Clin. Pharmnac 34: 130-138).
U.S Pat. No. 6,150,524 describes methods for the synthesis of other morphine derivatives, which are said to have strong analgesic properties and which can be administered by oral route.
It is also known that the combination of a compound binding to the μ receptors and a compound binding to the κ receptors, has a powerful analgesic effect without the side effects of physical dependence and respiratory depression (Rothman et al. 2000; J Subst Abuse Treat 19: 277-281; Shook et al., 1990 Am Rev Respir Dis 142: 895-909).
However, to the inventors' knowledge, no analgesic exists with an effectiveness comparable to that of morphine or M6G, but which does not have, or has fewer, side effects, in particular with regard to physical dependence and respiratory depression.